AB0515 PHARMACOKINETICS, SELECTIVITY PROFILE, AND EXPOSURE-RESPONSE RELATIONSHIP FOR EFFICACY AND SAFETY IN A PHASE 2 STUDY OF DEUCRAVACITINIB, AN ORAL, SELECTIVE, ALLOSTERIC TYK2 INHIBITOR, IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: T. Ide, M. Chiney, H. Y. T. Bach, V. Goti, B. Murthy, C. Hobar, Q. Zhao, U. Aras
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis <sup>[1,2]</sup>. Deucravacitinib binds to the unique TYK2 regulatory domain, conferring greater functional selectivity vs JAK inhibitors, which bind to the catalytic domain. Deucravacitinib showed superior efficacy vs placebo in a phase 2 trial in SLE (NCT03252587) <sup>[3]</sup>. <h3>Objectives</h3> This analysis assessed the pharmacokinetics (PK), selectivity profile compared to JAK inhibitors, and exposure-response (E-R) relationship for efficacy and safety of deucravacitinib in SLE. <h3>Methods</h3> In the phase 2 trial, patients with active SLE were randomized 1:1:1:1 to placebo or deucravacitinib (3 mg BID, 6 mg BID, 12 mg QD). PK analysis included pooled concentration data from 266 SLE patients and 328 phase 1 participants. IC<sub>50</sub> was determined by <i>in vitro</i> whole blood assays and plotted against PK profiles. E-R analyses included data from 356 patients. Logistic regression analyses assessed the relationship between deucravacitinib exposure and probability of achieving efficacy endpoints and safety events at weeks 32 and 48. <h3>Results</h3> Deucravacitinib PK in SLE patients was not meaningfully different from that in phase 1 participants. At 12 mg QD, deucravacitinib C<sub>max</sub> was 8-fold lower than JAK 1/3 IC<sub>50</sub> and 47-fold lower than JAK 2/2 IC<sub>50</sub> (<b>Figure 1</b>). In the E-R analyses, the probability of achieving SRI(4) and BICLA at week 32 increased with increasing deucravacitinib C<sub>minSS</sub>, with 3 mg BID providing near-maximal response. The E-R relationship for infection and infestation was relatively flat, while skin and subcutaneous tissue disorders increased with increasing deucravacitinib C<sub>minSS</sub>. These E-R relationships were similar at week 48. <h3>Conclusion</h3> Deucravacitinib PK in SLE patients is not meaningfully different from that in phase 1 participants. At clinically relevant exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 vs JAK 1/2/3. The deucravacitinib E-R relationships are well characterized for various efficacy endpoints and safety events. <h3>References</h3> [1]Armstrong A, et al. <i>J Am Acad Dermatol.</i> 2023;88(1):29-39. [2]Strober B, et al. <i>J Am Acad Dermatol.</i> 2023;88(1):40-51. [3]Morand E, et al. <i>Arthritis Rheumatol</i>. 2022 Nov 11 (Epub ahead of print). <h3>Acknowledgements</h3> This study was sponsored by Bristol Myers Squibb. <h3>Disclosure of Interests</h3> Takafumi Ide Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Manoj Chiney Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Huynh Yen Thanh Bach Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Vineet Goti Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Bindu Murthy Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Coburn Hobar Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Qihong Zhao Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Urvi Aras Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb.